The initial event in the life cycle of a virus is its interaction with specific receptors present on the surface of a cell. Understanding these interactions is important to our understanding of viral tropism and tissue specific pathology associated with viral disease. The human polyomavirus, JCV, is the etiologic agent of the fatal central nervous system (CNS) demyelinating disease, progressive mulifocal leukoencephalopathy (PML). PML occurs most frequently in immunosuppressed patients and its incidence has risen dramatically as a result of the AIDS pandemic. PML is the direct result of JCV multiplication in oligodendrocytes, the myelin producing cell in the CNS. In vivo, JCV has been detected in oligodendrocytes, astrocytes, lymphoid tissue, and peripheral blood of PML patients. In vitro, JCV infects human glial cells and, to a limited extent, human B lymphocytes. The initial step in infection of cells by JCV is at the level of attachment and entry. This critical event in the life cycle of JCV has not been investigated due to the lack of a convenient cell culture system for efficient propagation of JCV. We have overcome this problem by taking advantage of a chimeric JCV/SV40 hybrid virus that can be efficiently propagated in the human glial cell line, SVG. Our preliminary data demonstrate that highly purified JCV binds to a limited number of trypsin sensitive receptors on SVG cells. This has led us to hypothesize that infection of SVG cell by JCV is mediated by a specific proteinaceous cell surface receptor. This hypothesis will be tested by fulfilling the following three specific aims: 1) determine the biochemical nature of cell surface molecules that are important in mediating infection of SVG cells by JCV, 2) determine the relationship between virus binding to SVG cells and infectivity, and 3) identify a specific SVG cell surface receptor for JCV. The identification of a specific JCV receptor on SVG cells will yield new insights into the early events of the JCV life cycle. As this is a critical step in the establishment of infection this work may lead to the development of novel therapies to prevent or treat JCV-induced disease.